This revised Mentored Patient-Oriented Research Career Development Award (K23) application requests funding to support the training and research activities for Dr. Jess G. Fiedorowicz. His goal is to develop expertise in human cardiovascular physiology for the assessment of vascular function in patients with bipolar disorder. Vascular function represents an important intermediate phenotype in the development of atherosclerosis and has been demonstrated to be an independent predictor of cardiovascular disease. Bipolar disorders are associated with increased cardiovascular morbidity and mortality. The first-line, second- generation antipsychotics associated with weight gain (SGAWGs: risperidone, olanzapine, and quetiapine) have been associated with significant metabolic complications, which may increase risk for vascular disease. Assessment of vascular function may allow identification of clinically relevant mechanisms for the development of cardiovascular disease in patients with bipolar disorder. This research and training plan strongly emphasizes interdisciplinary and translational research as outlined by the NIH Roadmap. As a psychiatrist, Dr. Fiedorowicz seeks additional training in translational research applications in human vascular physiology and pharmacology, related statistical methodologies, and the ethical conduct and design of research. The research plan proposes a 26-week, prospective, naturalistic cohort study to examine the relationship of SGAWG use and vascular function in bipolar disorders by studying incident users of SGAWGs and non-users of antipsychotics with bipolar disorders. The primary aim of this study is to determine the magnitude and timeline of antipsychotic-induced changes in vascular function in incident users of SGAWGs. The methodology employed will allow for mechanistic investigation with particular focus on insulin resistance and visceral obesity. This application will provide a foundation for Dr. Fiedorowicz'long-term scientific goal of creating an independent program of interdisciplinary research addressing cardiovascular disease in bipolar disorders and the adverse cardiovascular effects of psychotropic medications.